Author: Mayank Bhandari
Bhandari, Mayank, 2008 ROLE OF GALANIN AND ITS ANTAGONISTS IN EXPERIMENTAL ACUTE PANCREATITIS, Flinders University, School of Medicine
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The broad aim of the studies described in this thesis was to evaluate the role of neuropeptide galanin in acute pancreatitis (AP). Treatment of AP is mainly symptomatic and supportive and no definitive pharmacological therapy for this disease is currently available. There are a number of studies in animal models of AP which demonstrate beneficial effect of a pharmacological agent in the management of AP. But most of these studies are limited to single species. The studies presented in the thesis evaluate the role of galanin and several of its antagonists in experimental AP in two different species. The initial part of the experimental work was performed in the possums, using a well established model of AP in the laboratory. Later, the experimental work has been carried out in the mouse. The overall hypothesis was that galanin plays a major role in the onset and/or progression of AP. In Chapter 2, the effect galanin or galantide administration, before and after AP induction on severity of AP in the possum model is described. The studies demonstrated that galantide decreased various indices of AP when administered prophylactically and therapeutically. 2 Chapter 3 outlines studies to determine if administration of galanin or galantide alters pancreatic vascular perfusion (PVP) during AP in the possum model. These studies suggested that in AP there is an initial fall in PVP, which is exacerbated by administration of galanin prior to onset of AP. Conversely, galantide administration prevented this decrease in PVP, and was associated with a rise in PVP through out the duration of the experiment. Chapter 4 describes preliminary studies on effect of galanin and galantide on pancreatic exocrine secretion. These demonstrated that galantide decreased hyperstimulated pancreatic exocrine secretion, but had no effect on the basal secretion. The subsequent studies are carried out using the caerulein mouse model of AP. The hypothesis has been tested in three different strains of mice, including a galanin gene knock-out (KO) strain. Chapter 5 outlines the effect galanin or galantide administration, before and after AP induction on the severity of AP in the caerulein mouse model. These studies revealed that galantide administration both prophylactically and therapeutically decreased the severity of AP in the mouse. In Chapter 6, the galanin gene KO were used to further test the hypothesis. These studies revealed that AP was less severe in the galanin KO mice, thereby suggesting a role for endogenous galanin in the onset and/or progression of AP. 3 Chapter 7 describes the effects of various galanin antagonist on the severity of AP in the caerulein mouse model. These studies revealed that galantide and M35 have beneficial effects in AP, i.e. reduced the indices of AP, whereas C7 and M40 had complex effects. Chapter 8 provides an overview of findings and discussion of their broader ramifications with future recommendations. Overall, the studies have demonstrated that galanin plays a major role in AP and galanin antagonists may be of potential therapeutic value in the management of AP.
Subject: Medicine thesis
Thesis type: Doctor of Philosophy
School: School of Medicine
Supervisor: James Toouli